This proposal describes a 5-year training program for the development of an academic career with a research focus in the adaptive immune response to skin bacteria and a clinical focus in inflammatory skin disease. Dr. Scharschmidt obtained an M.D. with thesis from the University of California, San Francisco (UCSF). Her graduate work as a medical student and Howard Hughes Medical Institute-NIH Research scholar focused on the role of filaggrin in skin barrier function, predisposition to allergic responses and the skin microbiome. This has uniquely prepared her to examine host-microbe interactions at the skin barrier. She recently graduated from a dermatology residency at UCSF where she was accepted into in the Physician-Scientist Training Program, an NIH supported T32 program combining clinical training with a post-doctoral research fellowship. During her post-doctoral work and over the past year as a junior faculty member in UCSF's department of dermatology, Dr. Scharschmidt has strategically sought out additional training and mentorship in both cutaneous immunology and microbiology. Through the proposed training program, she will expand upon her expertise in these areas as well as gain skills critical for professional development, ethical conduct of research, statistical analysis, and clinical care of patients with inflammatory skin disease. Dr. Scharschmidt's goal is to become an independent investigator studying the mechanisms responsible for establishing and maintaining immune tolerance to skin commensal bacteria. She will accomplish this through coursework, participation in seminars and conferences, national presentations and engagement in a mentored research project. Currently, little is known about the mechanisms of immune tolerance that allow skin lymphocytes to continuously sense antigens from commensal bacteria without eliciting destructive inflammation. The proposed research will focus on uncovering these cellular and molecular tolerance mechanisms, which are critical to preserving skin homeostasis and which, when broken, contribute to inflammatory skin disease. Using an innovative model that she developed to study the antigen-specific response to skin bacteria, Dr. Scharschmidt has made the novel observation that the neonatal period is a critical window for establishing tolerance to skin commensal bacteria. She has also discovered a unique and abundant population of activated regulatory T cells (Tregs) that enter the skin after the first week of life in a remarkably abrupt wave. In the proposed experiments, Dr. Scharschmidt will elucidate the functional role of these neonatal skin Tregs in establishing tolerance to skin commensals and dissect mechanisms responsible for their dramatic accumulation in neonatal skin. She also aims to establish and validate a humanized mouse model to study the adaptive immune response to commensal bacteria in human skin. The aggregate data will provide a major advancement in our understanding of how T cell-mediated immune responses to commensal bacteria are regulated and have the potential to establish a foundation for novel therapeutic approaches for inflammatory skin disease. Dr. Scharschmidt will benefit from a co-mentorship model that draws on the experience of a senior faculty member as well as the resources and scientific expertise of two highly promising junior faculty. Dr. Abul Abbas will be the senior mentor guiding Dr. Scharschmidt's scientific and career development. Dr. Abbas is Professor and Chairman of the Department of Pathology at UCSF and a world-renowned leader in the field of immune tolerance. His record of mentoring postdoctoral fellows and graduate students is outstanding. The research will be conducted in the laboratory of Dr. Michael Rosenblum, who is an Assistant Professor in the Department of Dermatology and a former trainee of Dr. Abbas. Dr. Rosenblum will provide the resources and space required for the proposed work as well as guidance on skin-specific aspects of immune tolerance. Dr. Michael Fischbach, an Assistant Professor of Bioengineering and Therapeutic Sciences will serve as the third co- mentor, providing scientific expertise on microbe-host interactions and mentorship on this aspect of Dr. Scharschmidt's career development. Dr. Abbas remains closely tied to the Rosenblum lab and participates in weekly lab meetings, providing continuity of mentorship. To enhance Dr. Scharschmidt's training, an advisory committee consisting of all three co-mentors as well as Dr. Theodora Mauro, a senior physician-scientist and cutaneous biologist, and Dr. Bruce Wintroub, chair of the UCSF dermatology department, will meet twice yearly to review her progress and support her career development. The proposed training program draws on the combined resources of the Rosenblum Laboratory, the UCSF Immunology Training Program, The UCSF Microbial Pathogenesis and Host Defense Training Program and the UCSF Department of Dermatology. This will provide an ideal setting for Dr. Scharschmidt's transition to an independent investigator